Pharmaceutical compositions containing rifaximin for treatment of vaginal infections

ABSTRACT

Vaginal pharmaceutical compositions administrable through the topical route, particularly in the form of vaginal foams and creams containing a therapeutically effective amount of rifaximin (Common International Denomination) are useful in the treatment of vaginal infections, particularly bacterial vaginosis.

BACKGROUND OF THE INVENTION

The present invention relates to rifaximin (Common InternationalDenomination) which is the compound 4-desoxy-4'-methyl-pyrido [1'2':1.2]imidazo [5.4-c] rifamycin SV, which is described in Italian Patent1,154,655 and in U.S. Pat. No. 4,341,785. The substance has beendescribed to be endowed with an antibacterial activity similar to theactivity of rifampin [Venturini A. P. and Marchi E., Chemiotherapia, 5(4), 257-256, (1986)]. However, its mechanism of action differs fromrifampin in that it is not absorbed through the systemic route afteroral administration [Venturini A. P., Chemotherapy, 29, 1-3, (1983) andCellai L. et al., Chemiotherapia, 3, (6), 373-377, (1984)] due to thezwitterionic nature of the compound, which cannot be absorbed by thegastrointestinal tract [Marchi E. et al., J. Med. Chem., 28, 960-963,(1985)].

Due to this particular pharamcokinetic behavior, rifaximin has notoxicity at a dose of 2000 mg/kg/os, when administered orally in rats,and therefore, on the basis of the microbiological pharmacodynamic andtoxicological data, this substance has been used as a drug for thetherapy of bacterial gastroenteritis, neurological symptoms and clinicalsymptoms of hepatic encefalopathy and for the pre- and post-surgicaltreatment of the gastrointestinal tract [Alvisi V. et al., J. Int. Med.Res., 15, 49-56, (1987), Testa R. et al., Drugs Exptl. Clin. Res., 11,387-392, (1985), Gruttadauria G. et al., Eur. Rev. Med. Pharm. Sci., 9,100-105, (1987)].

The present invention relates to a novel therapeutic use of rifaximin inthe treatment of vaginal infections, in particular bacterial vaginosis,because this antibiotic has now been shown to exhibit excellent activityin vitro (MIC) with respect to microorganisms such as Bacteroidesbivius-disiens, Gardnerella vaginalis, Mobiluncus spp., Neisseriagonorrhoeae, Lactobacillus spp. and Haemophilus ducreyi, in addition,Chlamydia trachomatis, another organism, infecting the vaginal tract,has shown susceptibility to rifaximin.

The main cause of vaginal symptoms in women is due to bacterialvaginosis, which is characterized by an increase in the vaginalsecretion of a white grayish color and which has a bad odor. Thisvaginal fluid shows the presence of bacterial flora which comprisesmainly anaerobic bacteria such as Gardnerella vaginalis and the speciesBacteroides, Mobiluncus and Lactobacillus, other aerobic bacteria suchas Haemophilus ducreyi and Neisseria gonorrhoeae may also cause vaginalsymptoms. Further the chemical composition shows an alteration in thepresence of organic acids with increase of succinates and decrease oflactates in addition to the presence of some amines which have bad odorsuch as putrescine, cadaverine and trimethylamine.

Bacterial vaginosis generally shows scanty or no inflammation of thevaginal epithelium and resembles more of an alteration of the bacterialvaginal ecosystem than a real and proper infection of tissues orepithelium. This pathology is currently being treated mainly withmetronidazole, clindamycin or ampicillin administered orally, but thismethod of use by the systemic route is frequently accompanied by seriousside effects. In fact, metronidazole exhibits serious side effectsparticularly on the blood and on the central nervous system so much thatin certain types of patients it has been necessary to discontinue thetreatment and authorities in the medical field have recommended thatwomen who use metronidazole should not breast feed (Martindale--TheExtra Pharmacopoeia--29th Edition--1989--page 667).

Clindamycin also exhibits serious side effects, particularly on thegastrointestinal tract with serious forms of diarrhea andpseudo-membranous colitis that can even lead to the death of the patient(Martindale--The Extra Pharmacopoeia--29th Edition--1989--pages198-199).

Rifaximin is not absorbed by the oral route [Venturini A. P.,Chemotherapy, 29, 1-3, (1983)] nor by topical application [Venturini A.P. et al., Drugs Exptl. Clin. Res., 13, 4, 233-6, (1987)]. Compared withdrugs currently used, rifaximin unquestionably exhibits a verysubstantial advantage, since there are no side effects.

DETAILED DESCRIPTION OF THE INVENTION

One objective of the present invention is to provide vaginalpharmaceutical compositions to be administered through the topicalroute, particularly vaginal foams and creams, containing atherapeutically effective amount of rifaximin, preferably between 50 mgand 500 mg, corresponding to the compound4-desoxy-4'-methylpyrido[1'2':1.2]imidazo[5,4-c]rifamycin SV describedin Italian Patent 1,154,655 and U.S. Pat. No. 4,341,785.

Another objective is to improve the method of treating a vaginalinfection, particularly bacterial vaginosis, with compositions of thepresent application, and to provide a method for the preparation of thepharmaceutical compositions.

All pharmaceutical composition commonly used for the treatment ofvaginal pathological conditions by the topical route may beadvantageously used within the scope of the present invention. Vaginalfoams, ointments, creams, gels, ovules, capsules, tablets andeffervescent tablets may be effectively used as pharmaceuticalcompositions containing rifaximin which are capable of beingadministered by the topical route for the treatment of vaginalinfections, including bacterial vaginosis.

The current invention relates to vaginal foam drug delivery system andcream as the preferred types of compositions and the clinical tests thathave been carried out with these two types of preparations. The bestclinical results have been achieved with the foam which, compared to theother pharmaceutical compositions, has unquestionable advantage ofpermitting rifaximin, which is not absorbed either by the systemic routenor by the topical route, the maximum possibility of contact with thevaginal mucosa, thus permitting the drug to achieve the best possiblebactericidal action with respect to the pathologic agents. In fact, thesystem of distribution of the drug through the foam permits rifaximin tobe distributed in an effective manner in the interior of the vagina,thus placing the drug in direct contact with the bacterial floraresponsible for the bacterial infections.

The vaginal foam drug delivery system consists of a cylindrical canistermade of aluminum, internally protected by a coating of epoxy-phenolicresins and provided with a valve and an applicator made of polyethylene.The formulation in the canister consists of suspension of micronizedrifaximin having a particle size lower than 100 microns (<100μ) inmineral, vegetable or semi-synthetic oil in the presence of a thickeningsubstance. The canister is closed with a valve through which apropellant gas is filled.

Many oily substances may be used in the present formulation. However,the main requirements for choice reside in their chemical stability andabsence of toxicity with respect to the vaginal mucosa.

The preferred oily substances are USP mineral oil, liquid paraffin,vaseline oil, triglycerides of caprylic and capric acid, such as thesubstance known as Myritol® 318 and polyoxyethylenated glycerides ofoleic acid, such as Labrafil® 2735 CS. The preferred thickeningsubstances are cetostearyl alcohol, which is a mixture of cetyl alcoholand stearyl alcohol, hydrogenated castor oil and beeswax. Gaseoushydrocarbons, pure or as a mixture, chlorofluorocarbons, fluorocarbons,carbon dioxide, nitrogen, inert gases or their mixtures may be used aspropellants. Dichlorodifluoromethane, propane, n-butane, isobutane ortheir mixtures, (55% of n-butane, 25% propane, 20% isobutane) known asPurifair® 3.2, are the preferred propellants within the scope of thepresent invention or formulation.

The composition of the suspension maintaining the active component byweight, consists preferably of 2% to 8% of micronized (<100μ) rifaximin,2% to 6% of the thickening agent and 86% of the oil base. The proportionof the propellant gas is between 60% and 100% of the weight of thesuspension.

The method of preparation of the formulation containing the vaginal foamdrug delivery system involves several steps. In the first step, thethickening agent is melted in an aliquot of the oil base of 50% to 60%.This step is carried out in a melter by heating the mixture to 50° to80° C. under stirring by agitation to obtain a practically homogeneoussolution.

In the second step, a suspension of micronized rifaximin (<100μ) isprepared in the remaining oil base by stirring at slow speed for 30minutes under a light vacuum (500 mm Hg) in a turbo-diffuser, which iscapable of operating under vacuum and is provided with a jacket forcooling and warming by water, equipped with an anchor-shaped stirringblade, a scraper and a whirling homogenizer.

The third step, the thickening agent (first step) is cooled to 40° to50° C. and then added to the rifaximin preparation (step two) under slowstirring while simultaneously creating a light vacuum and cooling bymeans of cold water in the jacket until room temperature is reached.

The last step provides for the sub-division by means of a fillingmachine of the suspension prepared in the preceding step in individualcanisters, which are then closed with a valve through which a propellantgas is introduced in an amount between 60% to 100% of the weight of thesuspension.

Creams and gels, other base formulations that may be used in the vaginaladministration of rifaximin, are prepared according to conventionalmethods for semi-solid compositions using excipients like vaseline,paraffin, vaseline oil, vegetable oils, animal oils, solid and liquidsynthetic glycerides, waxes, liquid alkylpolysiloxanes, lanolin, lanolinalcohols, sorbitan esters, fatty alcohols, liquid/solid polyethyleneglycols, propylene glycols, polyethylene, starch, derivatives ofcellulose and carboxyvinylpolymers.

Ovules, capsules, tablets and effervescent tablets are other formssuitable for the vaginal administration of rifaximin. Ovules are similarto suppositories, ovoidal shaped and the excipients mainly used aresemi-synthetic glycerides and polyethylene glycols and optionally alsoemulsifiers and surfactants.

The vaginal capsules are gelatinous envelopes within which is subdividedthe suspension which is generally anhydrous and contains liquidparaffin, vaseline, dimethylpolysiloxanes, vegetable oils andsemi-synthetic oils and thickening agents.

The tablets, shaped suitably for vaginal use, contain as main excipientslactose, starch, polyvinylpyrrolidone, cellulose derivatives, magnesiumstearate, glycocol. The effervescent tablets contain chemical components(i.e. sodium bicarbonate with citric acid or tartaric acid), which arenecessary to develop carbon dioxide in order to produce effervescence.

The efficacy of rifaximin in the treatment of vaginal infections hasbeen demonstrated by the determination of its activity in vitro (minimuminhibitory concentration) to inhibit pathogenic bacterial flora that ispresent in vaginal fluid of the patients having these pathologies andparticularly anaerobic bacteria such as Gardnerella vaginalis,Bacteroides bivius-disiens and the species Mobiluncus and Lactobacillusas well as aerobic bacteria such as Neisseria gonorrhoeae andHaemophilus ducreyi. The microbiologic activity has also beendemonstrated against Chlamydia trachomatis.

The tests of anti-bacterial activity in vitro of rifaximin have beencarried out on culture collections belonging to five hospitals,connected with three U.S. universities and two Canadian universities.Forty strains of Bacteroides bivius-disiens, 23 strains of Gardnerellavaginalis, 31 strains of the species Lactobacillus and 13 strains ofMobiluncus, 35 strains (from Iowa) and 25 strains (from Manitoba) ofNeisseria gonorrhoeae, 25 strains of Haemophilus ducreyi and 6 strainsof Chlamydia trachomatis have been analyzed. The determination of theminimum inhibitory concentration on the strains of the four types ofanaerobic bacteria has been carried out according to NCCLS M11-T2 method(National Committee for Clinical Laboratory Standards. Methods forantimicrobial testing of anaerobic bacteria--second edition: TentativeStandard. NCCLS M11-T2, Villanova, Pa. NCCLS; 1989) on agarWilken-Chalgren (Difco Laboratories, Detroit, Mich.) to which blood hasbeen added.

The determination of the minimum inhibitory concentration with respectto Neisseria gonorrhoeae has been carried out according to the NCCLSM7-A2 method (National Committee for Clinical Laboratory Standards.Methods for dilution antimicrobial susceptibility tests for bacteriathat grow aerobically--second edition; Approved Standard. NCCLS M7-A2.Villanova, Pa.:NCCLS; 1990).

The strains of Neisseria gonorrhoeae have been grown on chocolate agarfor 24 hours at 35° C. in the presence of 5% carbon dioxide. After eachmaterial has been isolated, it is applied on a plate based on agar GCcontaining appropriate dilution of antibiotic and incubated in anatmosphere containing carbon dioxide for 25 hours at 35° C.

The strains of Haemophilus ducreyi have been grown on chocolate agar for24 hours at 35° C. in an atmosphere of carbon dioxide. After eachmaterial has been isolated, it is applied on chocolate agar containingappropriate dilution of antibiotic (Hoban D. et al. "In vitro activityof lomefloxacin against Chlamydia trachomatis, Neisseria gonorrhoeae,Haemophilus ducreyi, Mycoplasma hominis and Ureaplasma urealyticum".Diagn. Microbiol. Infect. Dis. 12, 83S-86S, 1989). The plates areincubated in an atmosphere containing carbon dioxide with increasingmoisture at 35° C. for 48 hours.

Rifaximin has exhibited a significant in vitro activity with respect tothe vaginal bacterial flora with a minimum inhibitory concentrationvalue between 0.03 and 1 μg/mL with respect to the strains of the fourtypes of anaerobic bacteria (Gardnerella vaginalis, Bacteroidesbivius-disiens, Mobiluncus species and Lactobacillus species) and avalue of 0.12 and >16 μg/ml with respect to Neisseria gonorrhoeae,Chlamydia trachomatis M.I.C. were >20 μg/mL; Mycoplasma hominis andUreaplasma urealyticum were ≧64 μg/mL.

These values of minimum inhibitory concentration compare very favorablywith the values obtained with the strains of the four types of anaerobicbacteria in the case of the three antibiotics presently used in thesystemic route in the treatment of vaginal bacterial infections. Infact, metronidazole has shown values of minimum inhibitoryconcentrations between 1 and <16 μg/mL, ampicillin between 0.5 and >64μg/mL, and clindamycin between 0.06 and 4 μg/mL. In order to finallydemonstrate the real efficacy of the rifaximin compositions in thetreatment of vaginal bacterial pathologies, clinical testing has beencarried out in an Italian hospital with 35 patients affected bybacterial vaginosis using a vaginal foam, as described herein, and acream.

Vaginal infections represent a common disease of female genital organsvery frequently encountered in clinical practice. The incidence ofbacterial vaginosis is in a constant increase due to several factors,such as oral and local contraceptives, increased use of antibiotics,greater sexual freedom.

On the basis of the in vitro antimicrobial activity, which has shown theoptimum activity of rifaximin with respect to the common microorganismsresponsible for the vaginal infections, a study has been carried out forthe purpose of determining the clinical efficacy and microbiologicalefficacy of two compositions of rifaximin for vaginal use, the vaginalfoam drug delivery system and the cream as described in examples 4 and 7herein below.

The clinical and microbiological determination has been carried out with35 women who were not pregnant, of age, and affected by bacterialvaginosis. In each case, the diagnosis was made on the basis of thefollowing criteria: Presence of "clue cells" in an amount greater than20% with respect to the cells of the vaginal epithelium, together withat least two of the following three symptoms: homogeneous vaginalsecretion, pH of vaginal secretion greater than 4.7, fishy odor (amine)upon placing the vaginal secretion in contact with an aqueous solutionof 10% potassium hydroxide.

The patients affected by vaginal protozoan, mycotic, viral andgonococcal infections have been excluded in this clinical test.

The control of clinical symptoms (pruritus, burning, leukorrhea,dysuria, edema and vulvo-vaginal erythema), cytological examination ofthe vaginal secretion and microbiological examination of the vaginalsmear have shown that both pharmaceutical compositions that have beenadministered have effectively eliminated the clinical symptoms and havesubstantially reduced the percentage of "clue cells". Moreover, in anumber of patients, pathogenic bacterial flora, such as Gardnerellavaginalis, Mobiluncus spp. Bacteroides spp. and Streptococcus pyogeneshave been eliminated in the treatment with vaginal foam drug deliverysystem and the vaginal bacterial flora was normalized with thereappearance of the Doderlein's bacillus.

The vaginal foam drug delivery system exhibits therapeutic efficacy andpatient acceptability compared to the cream. The success of the vaginalfoam drug delivery system in eliminating the clinical symptoms 35 daysafter dosing is comprised between a minimum of 43.4% for vaginalerythema and 100% for dysuria, vulvar edema and erythema. The success ofthe cream is between a minimum of 60% for pruritus and a maximum of86.7% for leukorrhea. Microbiological efficacy of the foam at 35 daysafter treatment showed the disappearance of all the pathogenicmicroorganisms in 86.6% of the patients, while the cream caused thedisappearance of all pathogenic microorgamisms in 62.5% of the patients.

The vaginal foam drug delivery system was well accepted and tolerated byall patients. The cream formulation was also well tolerated although 1patient treated with the cream withdrew from the study due toirritation. In addition, the patients have shown to be more pleased withthe treatment with the vaginal foam because of the greater ease ofmanipulation and application and for the pleasant sensation of coolness,the so-called "cooling effect" which is typical of this type offormulation.

The results of the clinical investigation have demonstrated the efficacyof both pharmaceutical compositions containing rifaximin and inparticular, of the vaginal foam drug delivery system in the treatment ofvaginal infections and bacterial vaginosis. The results that have beenobtained are similar to the results obtained with the conventional drugsused through the systemic route, such as metronidazole, clindamycin andampicillin, but with the substantial advantage being obtained that thetreatment is totally devoid of the disadvantageous side effectscharacteristic of the antibiotics mentioned above.

The examples reported herein below further illustrate the object of thepresent invention, but they should not be considered as a limitation toit.

EXAMPLE 1 Antibacterial activity of rifaximin on microorganisms presentas pathogenic agents in vaginal infections

The antibacterial activity in vitro (Minimum InhibitoryConcentration--MIC) of rifaximin has been evaluated with many strains offour active pathogenic agents present in vaginal infections and comparedwith three antibiotics (metronidazole, ampicillin, clindamycin) used inthe systemic treatment of vaginal infections. Moreover, the MIC ofrifaximin has been evaluated also with strains of Chlamydia trachomatis,Mycoplasma hominis, Ureaplasma urealyticum, Neisseria gonorrhoeae andHaemophilus ducreyi.

Forty strains of Bacteroides bivius-disiens, 23 strains of Gardnerellavaginalis, 31 strains of Lactobacillus spp., 13 strains of Mobiluncusspp., 6 strains of Chlamydia trachomatis, 60 strains of Neisseriagonorrhoeae and 25 strains of Haemophilus ducreyi were obtained byculture collections supplied from:

A. Department of Pathology, University of Iowa College of Medicine, IowaCity, Iowa

B. St. Francis Regional Medical Center, Wichita, Kans.

C. New England Deaconess Hospital, Boston, Mass.

D. University of Manitoba Health Science Center, Winnipeg, Manitoba

E. University of Alberta, Alberta, Canada.

The strains of anaerobic microorganisms have been subjected to the invitro tests with rifaximin, metronidazole, ampicillin and clindamycinusing the previously described method (National Committee for ClinicalLaboratory Standards. Methods for antimicrobial testing of anaerobicbateria--second edition; Tentative Standard. NCCLS M11-T2, Villanova,Pa. NCCLS; 1989) using agar Wilken-Chalgren (Difco Laboratories,Detroit, Mich.) to which blood has been added.

The strains of the other microorganisms have been subjected to the invitro tests with rifaximin. The determination of the MIC with respect toNeisseria gonorrhoeae has been carried out according to the NCCLS M7-A2method, while the determination of th MIC with respect to Chlamydiatrachomatis, Mycoplasma hominis, Ureaplasma urealyticum and Haemophilusducrey has been carried out according to Hoban D. et al. "In vitroactivity of lomefloxacin against Chlamydia trachomatis, Neisseriagonorrhoeae, Haemophilus ducreyi, Mycoplasma hominis and Ureaplasmaurealyticum." Diagn. Microbiol. Infect. Dis., 12, 83S-86S (1989).

The results of the tests of antimicrobial activity expressed as MIC inμg/mL are reported in Table I and demonstrate the positive behavior invitro of rifaximin compared with the three systemic antibiotics commonlyused.

                                      TABLE 1                                     __________________________________________________________________________                         MIC (μg/mL)                                                   Number                 Range of                                               of   Antimicrobial     Concentration                                  Microorganism                                                                         Strains                                                                            Agents  50%  90%  Value                                          __________________________________________________________________________    Bacteroides                                                                           40   Rifaximin                                                                             0.12 0.25 ≦0.03-0.5                               bivius-disiens                                                                             Ampicillin                                                                            4    64   ≦0.5->64                                             Clindamycin                                                                           ≦0.06                                                                       <0.06                                                                              ≦0.06                                                Metronidazole                                                                         2    4    0.5-8.0                                        Gardnerella                                                                           23   Rifaximin                                                                             0.5  1    0.25-1.0                                       vaginalis    Ampicillin                                                                            ≦0.5                                                                        <0.5 ≦0.5-2                                               Clindamycin                                                                           ≦0.06                                                                       <0.06                                                                              ≦0.06-0.25                                           Metronidazole                                                                         >16  >16  4->16                                          Lactobacillus                                                                         31   Rifaximin                                                                             0.12 0.5  ≦0.3-1                                  spp.         Ampicillin                                                                            ≦0.5                                                                        1    ≦0.5-2                                               Clindamycin                                                                           0.25 4    ≦0.06-4                                              Metronidazole                                                                         >16  >16  >16                                            Mobiluncus                                                                            13   Rifaximin                                                                             ≦0.03                                                                       <0.03                                                                              ≦0.03                                   spp.         Ampicillin                                                                            ≦0.5                                                                        4    ≦0.5-4                                               Clindamycin                                                                           ≦0.06                                                                       <0.06                                                                              ≦0.06                                                Metronidazole                                                                         >16  >16  1->16                                          Chlamydia                                                                              6   Rifaximin                                                                             --   <20  <10-20                                          trachomatis                                                                  Mycoplasma                                                                            20   Rifaximin                                                                             64   ≧64                                                                         ≧64                                     hominis                                                                       Ureaplasma                                                                            25   Rifaximin                                                                             64   >64  32->64                                         urealyticum                                                                   Neisseria                                                                             60   Rifaximin                                                                             0.25 16   0.12->16                                       gonorrhoeae                                                                   Haemophilus                                                                           25   Rifaximin                                                                             0.25 0.5  0.03-0.5                                       ducreyi                                                                       __________________________________________________________________________

EXAMPLE 2 Clinical evaluation of a vaginal foam and a cream containingrifaximin

The clinical evaluation has been carried out in San Martino Hospital inGeneva with 30 women, not pregnant, affected by bacterial vaginosis. Thediagnosis of bacterial vaginosis was made on the basis of the presenceof "clue cells" in an amount greater than 20% of the cells of thevaginal epithelium and the simultaneous presence of at least two of thefollowing 3 factors:

A. Homogeneous vaginal secretion,

B. pH of the vaginal secretion greater than 4.7,

C. Fishy odor of the vaginal secretion.

Patients affected by vaginal infections of protozoan, fungal, viral andgonococcal origin were excluded. The patients were divided at random intwo groups, one group being treated with the vaginal foam (Example 4)and the other group treated with cream (Example 7). The treatmentconsisted of one application prior to going to bed for five consecutivenights.

The microbiological, clinical and cytological controls were establishedat admission (Visit 1), 5 days after the end of the therapy (Visit 2)and 35 days after the end of the therapy (Visit 3). The last controlsconfirmed the results obtained in the Visit 2 controls.

The scoring measure is comprised between 0, absence of symptoms, and 3,serious symptoms, including subjective symptoms and those observedthrough objective examination. The results confirming the therapeuticactivity of rifaximin in the treatment of bacterial vaginosis arereported in Table 2 for the vaginal foam and in Table 3 for the cream.

The therapeutic efficacy of both formulations in shown in Table 4 andshows a clear improvement for both compositions. The vaginal foam drugdelivery system had a better (86.7%) cure rate compared to the creamformulation (56.2%).

Table 5 reports the results of microbiological tests carried out withbacterial cultures present in the vaginal smears removed from thepatient prior to the beginning of the treatment (Visit 1) and after thetreatment (Visits 2 and 3). Prior to the beginning of treatment, thepathogenic bacterial flora was constituted essentially by Gardnerellavaginalis, Mobiluncus spp. and with less frequency by Streptococcuspyogenes and Bacteroides spp.

                  TABLE 2                                                         ______________________________________                                        Clinical results with women affected by bacterial vaginosis                   treated with vaginal foam prepared according to example 4.                                             %             %                                                               CHANGE        CHANGE                                                          BE-           BE-                                                             TWEEN         TWEEN                                  SIGNS &  VISIT   VISIT   VISITS  VISIT VISITS                                 SYMPTOMS 1       2       1 & 2   3     1 & 3                                  ______________________________________                                        Pruritus 1.15    1.00    13.0    0.54  53.0                                   Burning  1.77    0.61    65.5    0.08  95.5                                   Leukorrhea                                                                             2.46    1.08    56.1    0.85  65.4                                   Dysuria  1.15    0.00    100.0   0.00  100.0                                  Vulvar   0.92    0.31    66.3    0.00  100.0                                  Edema                                                                         Vulvar   1.08    0.08    92.6    0.00  100.0                                  Erythema                                                                      Vaginal  0.69    0.08    88.4    0.08  88.4                                   Edema                                                                         Vaginal  1.00    0.91    71.3    0.61  43.4                                   Erythema                                                                      ______________________________________                                    

                  TABLE 3                                                         ______________________________________                                        Clinical results with women affected by bacterial vaginosis                   treated with cream prepared according to example 7.                                                    %             %                                                               CHANGE        CHANGE                                                          BE-           BE-                                                             TWEEN         TWEEN                                  SIGNS &  VISIT   VISIT   VISITS  VISIT VISITS                                 SYMPTOMS 1       2       1 & 2   3     1 & 3                                  ______________________________________                                        Pruritus 1.50    0.90    40.0    0.60  60.0                                   Burning  1.60    0.80    50.0    0.40  75.0                                   Leukorrhea                                                                             2.50    0.11    95.6    0.11  95.6                                   Dysuria  1.10    0.10    90.00   0.10  90.9                                   Vulvar   1.20    0.40    66.7    0.20  83.3                                   Edema                                                                         Vulvar   1.00    0.20    80.0    0.20  80.0                                   Erythema                                                                      Vaginal  1.20    0.30    75.0    0.10  91.7                                   Edema                                                                         Vaginal  1.50    0.60    60.0    0.30  80.0                                   Erythema                                                                      ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                        Results of cytological examination carried out with women                     affected by bacterial vaginosis.                                                                NUMBER OF PATIENTS                                          PATIENT STATUS      FOAM      CREAM                                           ______________________________________                                        Enrolled            17        18                                              Curred at Visit 2   13        9                                               Curred at Visit 3   13        9                                               % Curred at Visit 3 86.7%     56.2%                                           Treatment Failure   2         6                                               Dropped Due to Irritation                                                                         0         1                                               Lost to Follow-Up   2         2                                               ______________________________________                                    

                                      TABLE 5                                     __________________________________________________________________________    Culture results of patients treated with foam drug delivery                   system and cream.                                                                           VISIT 1  VISIT 2  VISIT 3                                                     FOAM                                                                              CREAM                                                                              FOAM                                                                              CREAM                                                                              FOAM                                                                              CREAM                                     PATHOGENS ISOLATED                                                                          n = 17                                                                            n = 18                                                                             n = 15                                                                            n = 16                                                                             n = 13                                                                            n = 10                                    __________________________________________________________________________    Gardnerella   14  15   1   5    0   0                                         Gardnerella & 3   2    0   0    0   0                                         Mobiluncus                                                                    Gardnerella & 0   0    1   1    0   0                                         Streptococcus                                                                 Streptococcus 0   0    1   1    0   0                                         Enterobacter  0   na   1   na   0   na                                        Gardnerella & 0   0    0   1    1   1                                         Candida                                                                       __________________________________________________________________________

EXAMPLE 3 System of distribution of foam containing rifaximin to beadministered vaginally

    ______________________________________                                        Composition of Each Canister                                                  ______________________________________                                        Rifaximin                200 mg                                               Cetyl stearyl alcohol USP                                                                              160 mg                                               Mineral oil USP         3640 mg                                               Mixture of n-butane/propane/isobutane                                                                 3150 mg                                               55:25:20 (Purifair ® 3.2)                                                 ______________________________________                                    

In a stainless steel container provided with an external jacket forwarming and with a stirring blade, melt 3.2 kg cetyl stearyl alcohol USPin 43.8 kg mineral oil USP to a temperature of +65°±5° C. under stirringup to complete solution. In a turbo vacuum diffuser made of stainlesssteel provided with a jacket for heating and cooling with water and alsoprovided with a stirring blade, scraper and central turbo homogenizer,introduce 29 kg mineral oil USP and 4 kg micronized (<100μ) rifaximin.The material is kept under stirring at a low rate for 30 minutes under alight vacuum (500 mm of mercury). A solution of cetyl stearyl alcohol inmineral oil USP, previously cooled to 45° C., is added to thissuspension with continuous stirring under light vacuum for an additional10 minutes while simultaneously cooling the mixture to room temperature.The mixture is subdivided by means of a filling machine in 20,000canisters, which are then closed with a polyethylene valve and filledwith propellant gas Purifair® 3.2 and finally a delivery means providedwith a polyethylene tube is inserted in the valve.

EXAMPLE 4 Pharmaceutical composition of foam containing rifaximin to beadministered vaginally

    ______________________________________                                        Composition of each canister                                                  ______________________________________                                        Rifaximin             200 mg                                                  Cetyl stearylic alcohol USP                                                                         160 mg                                                  Liquid paraffin      3640 mg                                                  Dichlorofluoromethane                                                                              3000 mg                                                  ______________________________________                                    

The canisters are made in a manner similar to example 3.

EXAMPLE 5 Pharmaceutical composition of foam containing rifaximin to beadministered vaginally

    ______________________________________                                        Composition of each canister                                                  ______________________________________                                        Rifaximin               200 mg                                                Cetyl stearylic alcohol USP                                                                           160 mg                                                Triglycerides of caprylic & capric acid                                                              3640 mg                                                (Myritol ® 318)                                                           Mixture n-butane/propane/isobutane                                                                   3300 mg                                                5:25:20 (Purifair ® 3.2)                                                  ______________________________________                                    

The canisters are made in a manner similar to Example 3.

EXAMPLE 6 Pharmaceutical composition of foam containing rifaximin to beadministered vaginally

    ______________________________________                                        Composition of each canister                                                  ______________________________________                                        Rifaximin                  100 mg                                             Cetyl stearylic alcohol USP                                                                              160 mg                                             Polyoxyethylenated glycerides of oleic acid                                                             3740 mg                                             (labrafil ® 2735 CS)                                                      Mixture n-butane/propane/isobutane                                                                      3200 mg                                             55:25:20 (Purifair ® 3.2)                                                 ______________________________________                                    

The canisters are produced in the same manner as described in Example 3.

EXAMPLE 7 Pharmaceutical composition of cream containing rifaximin

    ______________________________________                                        Percent of composition of the cream                                           ______________________________________                                        Rifaximin           5%                                                        White vaseline      10%                                                       Liquid paraffin     72%                                                       White wax           3%                                                        Hydrogenated caster oil                                                                           5%                                                        Methyl glucose dioleate                                                                           5%                                                        ______________________________________                                    

In a turbo diffuser similar to the apparatus used in Example 3, amixture consisting of white vaseline, liquid paraffin, white wax andmethyl glucose dioleate is melted by warming to a temperature of 72° C.under slow stirring. Hydrogenated castor oil is added to the mixture,which is then homogenized with a central turbo homogenizer. Aftercooling to room temperature, micronized rifaximin (<100μ) is added tothe mixture and then homogenized with the turbo diffuser under a lightvacuum of 500 mm of mercury. The resulting cream is filled into suitablecontainers.

EXAMPLE 8 Pharmaceutical composition of vaginal ovules containingrifaximin

    ______________________________________                                        Composition of each ovule                                                     ______________________________________                                        Rifaximin             200 mg                                                  Solid semi-synthetic glycerides                                                                    1600 mg                                                  ______________________________________                                    

In a stainless steel container equipped with exterior jacket for warmingand cooling, the solid semi-synthetic glycerides is placed, along withthe micronized (<100μ) rifaximin. The mixture is homogenized with theUltra Turax homogenizer and then divided into individual containers ofthe shape suitable for vaginal use.

EXAMPLE 9 Pharmaceutical composition of vaginal capsules containingrifaximin

    ______________________________________                                        Composition of each vaginal capsule                                           ______________________________________                                        Rifaximin         150 mg                                                      Liquid glycerides 900 mg                                                      Silica             5 mg                                                       ______________________________________                                    

A suspension of micronized (<100μ) rifaximin and silica is homogenizedin a stainless steel container containing the liquid glycerides by meansof the homogenizer Ultra Turax. The suspension is then poured intogelatin capsules for vaginal use.

EXAMPLE 10 Pharmaceutical composition of vaginal tablets containingrifaximin

    ______________________________________                                        Composition of each vaginal capsule                                           ______________________________________                                        Rifaximin          200 mg                                                     Lactose            1200 mg                                                    Corn starch        200 mg                                                     Polyvinylpyrrolidone                                                                              50 mg                                                     Magnesium stearate  12 mg                                                     Talcum              7 mg                                                      ______________________________________                                    

Micronized (<100μ) rifaximin is granulated with lactose, corn starch anda solution of polyvinylpyrrolidone in ethyl alcohol. The granulates aredried in a dryer and screened on a 1 mm screen. To the granulate addtalcum and magnesium stearate and the mixture is compressed to obtaintablets of the shape suitable for vaginal use.

EXAMPLE 11 Pharmaceutical composition of effervescent vaginal tabletscontaining rifaximin

    ______________________________________                                        Composition of each vaginal effervescent capsule                              ______________________________________                                        Rifaximin              100 mg                                                 Citric acid            260 mg                                                 Sodium bicarbonate     300 mg                                                 Magnesium stearate      10 mg                                                 Talcum                  8 mg                                                  Polyvinylpyrrolidone:ethyl alcohol                                                                    35 mg                                                 ______________________________________                                    

Polyvinylpyrrolidone is dissolved in ethyl alcohol. A mixture of citricacid and one-half of the micronized (<100μ) rifaximin is granulated withone-half of the polyvinylpyrrolidone:alcohol solution. The otherone-half of the polyvinylpyrrolidone:alcohol solution is used togranulate the mixture formed by the sodium bicarbonate and the remaininghalf of rifaximin. The two granulates are dried separately, screened ona 1 mm screen, and then mixed together with talcum and magnesiumstearate. The resulting mixture is compressed to obtain tablets of theshape suitable for vaginal use.

What is claimed is:
 1. A method of treatment of a vaginal infectionwhich consists of administering topically to a subject in need oftreatment a vaginal pharmaceutical composition containing atherapeutically effective amount of Rifaximin in the form of a foam, acream, a gel, a vaginal ovule or a vaginal capsule.
 2. The methodaccording to claim 1 wherein said treatment is with said foam, the floraof Gardnerella vaginalis, Mobiluncus spp., Bacteroides spp. andStreptococcus pyogenes are eliminated and the vaginal bacterial flora isnormalized with the reappearance of the Doderlein's bacillus.
 3. Themethod according to claim 1 wherein said vaginal infection consists ofbacterial vaginosis.
 4. The method of treatment of a vaginal infectionaccording to claim 1 which consists of applying by the topical route apharmaceutically effective amount of Rifaximin to a patient in need ofsaid treatment.
 5. The method according to claim 4 wherein said vaginalinfection consists of bacterial vaginosis.
 6. The method according toclaim 4 wherein said topical application is carried out by means of avaginal foam.
 7. The method according to claim 4 wherein said topicalapplication is carried out by means of a cream.